N-aryl-n-(1-substituted-3-alkoxy-4-piperidinyl)amides and pharmaceutical compositions and methods employing such compounds

ABSTRACT

This invention pertains to novel N-aryl-N-[N-substituted 3-alkoxy-4-piperidinyl]amides useful as analgesics, and methods of administering analgesia, which comprises the systemic administration to mammals of such compounds, and pharmaceutical compositions containing such compounds, wherein the novel compounds have the general formula: ##STR1## including optically active isomeric forms, cis/trans isomeric forms and the pharmaceutically acceptable acid addition salts thereof, wherein: 
     R is an aryl group selected from the group consisting of phenyl and substituted phenyl, wherein the substituents on the phenyl group are independently selected from the group consisting of halogen, lower-alkyl, lower-alkoxy, and combinations thereof; 
     R 1  is an alkyl group selected from the group consisting of lower-alkyl, lower-alkenyl, and lower-alkoxy lower-alkyl, each alkyl group having from 1 to 6 carbon atoms; 
     R 2  is a member selected from the group consisting of phenyl lower-alkyl, thienyl lower-alkyl, pyrazolyl lower-alkyl, tetrazolyl lower-alkyl, 4,5-dihydro-5-oxo-1H-tetrazolyl lower-alkyl, 1,3-dihydro-1,3-dioxo-2H-isoindolyl lower-alkyl, and 2,3-dihydro-2-oxo-1H-benzimidazolyl lower-alkyl; and 
     R 3  is a member selected from the group consisting of hydrogen, lower-alkyl and lower-alkyl aryl.

This is division of application Ser. No. 351,360, file May 12, 1989, nowU.S. Pat. No. 4,994,471.

The present invention relates to N-arylN-[1-substituted-3-alkoxy-4-piperidinyl]amides and pharmaceuticalcompositions and methods employing such compounds. In particular, thisnew class of compounds possesses potent analgesic and anestheticproperties.

BACKGROUND OF THE INVENTION

A number of patents disclose certainN-aryl-N(1-substituted-4-piperidinyl) amides having analgesic activity.For example, U.S. Pat. Nos. 3,998,834, 3,164,600, and 4,167,574, issuedto Janssen et al. and assigned to Janssen Pharmaceuticals N.V., disclosecertain N-phenyl-N-[1-(aryl-substituted)-4piperidinyl]amide compounds,N-aryl-N-[1-(arylalkyl)-4-piperidinyl] amides andN-aryl-N-[1-(tetrazolyl-substituted)-4-piperidinyl]amides useful asanalgesics. U.S. Pat. No. 4,584,303, issued to Huang et al. and assignedto The BOC Group, Inc., discloses certainJ-phenyl-N-[1-(heterocyclic)-4-piperidinyl]amide compounds useful asanalgesics.

U.S. Patent No. 4,138,492, issued to Noverola et al. and assigned toAnphar, S.A., discloses certainN-[4'(1'-arylalkyl)piperidinyl]-4-amino-5-halo-2alkoxy benzamidecompounds. Van Daele et al., Drug Develooment Research, 225-232 (1986),discloses the preparation of certain3-hydroxy-4,4-dimethoxy-1phenylmethyl piperidine derivatives.

SUMMARY OF THE INVENTION

This invention pertains to novelN-aryl-N-[1-substituted-3-alkoxy-4-piperidinyl]amides useful asanalgesics, and methods of administering analgesia, which comprises thesystemic administration to mammals of such compounds, and pharmaceuticalcompositions containing such compounds, wherein the novel compounds havethe general formula: ##STR2## including optically active isomeric forms,cis/trans isomeric forms and the pharmaceutically acceptable acidaddition salts thereof, wherein:

R is an aryl group selected from the group consisting of phenyl andsubstituted phenyl, wherein the substituents on the phenyl group areindependently selected from the group consisting of halogen, lower-alkyllower-alkoxy, and combinations thereof;

R₁ is an alkyl group selected from the group consisting of lower-alkyl,lower-alkenyl, and lower-alkoxy lower-alkyl, each alkyl group havingfrom 1 to 6 carbon atoms;

R₂ is a member selected from the group consisting of phenyl lower-alkyl,thienyl lower-alkyl, pyrazolyl lower-alkyl, tetrazolyl Iower-alkyl,4,5-dihydro-5-oxo-1H-tetrazolyl lower-alkyl, 1,3-dihydro-1,3-dioxo-2H-isoindolyl (N-phthalimidyl) lower-alkyl, and2,3-dihydro-2-oxo-1H-benzimidazolyl lower-alkyl; and

R₃ is a member selected from the group consisting of hydrogen,lower-alkyl and lower-alkyl aryl.

DETAILED DESCRIPTION OF THE INVENTION

The compounds of the present invention possess very desirable analgesicactivities. In particular, the inventive compounds have central nervoussystem depressant properties which include analgesia, hypnosis,sedation, muscle relaxation, increased pain threshold, and barbiturateand/or general anesthetic potentiation. Many of the compounds providehighly potent analgesia with immediate onset and a short duration ofaction. These properties are highly desirable in circumstances whereacute severe pain must be eliminated over a short period of time, suchas in anesthesiology. The preferred compounds of the present inventionhave been found to provide reduced rigidity at high doses, superiormotor coordination recovery, or less respiratory and/or cardiovasculardepressive activity when compared to fentanyl,N-phenyl-N-[1-(2-phenylethyl)-4-piperidinyl]propanamide.

The compounds of the present invention may be used together with apharmaceutically acceptable carrier to provide pharmaceuticalcompositions and can be administered to mammals such as man in amountssufficient to provide analgesic effects

As set out above, the analgesic compounds of the present invention havethe general formula (I): ##STR3## including optically active isomericforms, cis/trans isomeric forms and the pharmaceutically acceptable acidaddition salts thereof, wherein R, R₁, R₂ and R₃ are defined as setforth below.

Group R in Formula (I) above is an aryl group selected from the groupconsisting of phenyl and substituted phenyl, wherein the substituents onthe phenyl group are independently selected from the group consisting ofhalogen, lower-alkyl, lower-alkoxy, and combinations thereof. Thepreferred substituents are selected from the group consisting of fluoroand methoxy. The preferred position for attachment of a substituent tothe phenyl ring is at the 2 (ortho) position. In a preferred embodiment,the R group is a member selected from the group consisting of phenyl,2-fluorophenyl and 2-methoxyphenyl.

Group R₁ in Formula (I) above is an alkyl group selected from the groupconsisting of lower-alkyl, lower-alkenyl, and lower-alkoxy lower-alkyl,each alkyl group having from I to 6 carbon atoms. In a preferredembodiment, the R₁ group is a member selected from the group consistingof methyl, ethyl, methoxymethyl and 1-methoxyethyl.

Group R₂ in Formula (I) above is a substituted or unsubstituted ringsystem selected from the group consisting of phenyl lower-alkyl,monocyclic heterocyclic lower-alkyl ring systems having 5 to 6 ringmember atoms and fused bicyclic and tricyclic heterocyclic lower-alkylring systems having 5 to 6 ring member atoms in each ring of thepolycyclic ring system. The heteroatom may be selected from the groupconsisting of nitrogen, sulfur and oxygen.

In a preferred embodiment, group R₂ in Formula (I) above is a memberselected from the group consisting of phenyl lower-alkyl, thienyllower-alkyl, pyrazolyl lower-alkyl, tetrazolyl lower-alkyl,4,5-dihydro-5-oxo-1H-tetrazolyl lower-alkyl,1,3-dihydro-1,3-dioxo-2H-isoindolyl (N-phthalimidyl) lower-alkyl, and2,3-dihydro-2-oxo-1H-benzimidazolyl lower-alkyl.

In a more preferred embodiment, group R₂ in Formula (I) above is amember selected from the group consisting of phenyl lower-alkyl,2-thienyl lower-alkyl, 3-thienyl lower-alkyl, 1H-pyrazol-1-yllower-alkyl, 2H-tetrazol-2-yl lower-alkyl,4,5-dihydro-5-oxo-1H-tetrazol1-yl lower-alkyl which is substituted inthe 4-position with lower-alkyl, 1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl(N-phthalimidyl) lower-alkyl, and 2,3-dihydro-2-oxo-1H-benzimidazolyllower-alkyl which is substituted in the 3position with lower-alkyl.

In a most preferred embodiment, group R₂ in Formula (I) above is amember selected from the group consisting of phenylmethyl,2-phenylethyl, 2-(2thienyl)ethyl, 2-(1H-pyrazol-1-yl)ethyl,2-(2H-tetrazol2-yl)ethyl,2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1yl)ethyl, and2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl) ethyl.

The phenyl or heterocyclic ring may be unsubstituted or substituted,wherein the substituent group is a member independently selected fromthe group consisting of halogen, lower-alkyl, lower-alkoxy, halogenatedlower-alkyl, and combinations thereof In a preferred embodiment, thesubstituent group is a member selected from the group consisting offluoro, chloro, iodo, methyl, ethyl, isopropyl, methoxy,trifluoromethyl, and combinations thereof.

The lower-alkyl group is a member selected from the group consisting ofbranched or unbranched hydrocarbon groups containing from I to 7 carbonatoms. In a preferred embodiment, the lower-alkyl group is a memberselected from the group consisting of methyl and ethyl.

Group R₃ in Formula (I) above is a member selected from the groupconsisting of hydrogen, loweralkyl and lower-alkyl aryl. In a preferredembodiment, the R₃ group is a member selected from the group consistingof hydrogen, methyl and phenylmethyl.

The term lower-alkyl groups, as used herein, means branched orunbranched hydrocarbon groups containing from 1 to 7 carbon atoms. Theterm loweralkoxy groups, as used herein, means branched or unbranchedhydrocarboxy groups containing from 1 to 7 carbon atoms. Preferredheterocyclic groups include from 2 to 12 member atoms and can includethe substituents discussed above in connection with heterocyclic groups.The term halogen, as used herein, refers to the chemically relatedelements consisting of, fluorine, chlorine, bromine and iodine.

The compounds of the present invention which have at least oneasymmetric carbon atom can exist in optically active isomeric forms. Forexample, in compounds in which R₂ is a 2-phenyl-1-propyl or1-phenyl2-propyl group, etc., the carbon adjacent to the piperidinylnitrogen is an asymmetric carbon atom and such compounds can thereforeexist in optical active isomeric (enantiomeric) forms. Such isomericforms can be isolated from the racemic mixtures by techniques known tothose skilled in the art.

The 3-alkoxypiperidine substituted compounds of the present inventionexist in cis and trans form. Such compounds can be used as a mixture cfsuch forms but many times one form is more active than the other or oneform has other desirable characteristics. Thus many times it isdesirable to resolve the cis/trans mixture. This resolution can beaccomplished by techniques conventional in the art for such purpose,e.g., chromatographic techniques such as column chromatography or highpressure liquid chromatography or simple recrystallization techniques.

The compounds of the present invention can be prepared by variousmethods. In general, the desired compounds having Formula (I) above canbe prepared by reacting a compound having the formula: ##STR4## with acompound having the formula:

    R.sub.1 --CO--X or (R.sub.1 CO).sub.2 O

or by reacting a compound having the formula: ##STR5## with a compoundhaving the formula:

    R.sub.2 X

wherein the substituent groups R, R₁, R₂ and R₃ have the definitions setout above, and X represents halide or its reactive equivalent. Examplesof halide reactive equivalents are toluene sulfonate, phenyl sulfonate,methyl sulfonate and the like.

In the first reaction, when the R₂ group is phenylmethyl (benzyl), thephenylmethyl group can be cleaved by hydrogenolysis or by reaction with1-chloroethyl chloroformate followed by hydrolysis with methanol, seeR.A. Olofson et al., J. Oro. Chem., 49, pp. 2081-2082 (1984), andreplaced with other R₂ groups such as furanyl lower-alkyl, pyrazoyllower-alkyl and the like. The preparation of secondary amines of thelatter type has been described by P. G. H. Van Daele et al.,Arzneim-Forsch. Drug Res., 6, p. 1521, (1976).

Several convenient routes for the preparation of the compounds of theinvention begin with known piperidone starting materials as shown below:##STR6##

The compound 1-(2-phenylethyl)-4-piperidone (1), can be preparedaccording to the procedure published by A.H. Becket, A.F. Casey and G.Kirk, J. Med Pharm. Chem., Vol. 1, p. 37 (1959). The compound1-phenylmethyl-4-piperidone (2), can be prepared in an analogous mannerby the procedure described by C.R. Ganellin and R.G. Spickch, J. Med.Chem., Vol. 8, p. 619 (1965) or P.M. Carabateas and L. Grumbach, J. Med.Pharm. Chem., Vol. 5, p. 913 (1962).

In one example of a method for preparing the compounds of the presentinvention, 1-phenylmethyl-4piperidone or1-(2-(phenyl)ethyl)-4-piperidone is reacted with iodobenzene diacetateto form ketal intermediate (3a), see Van Daele et al., Drug DevelopmentResearch, 8, pp 225-232 (1986) and Moriarty et al., Tetrahedron Letters.25. pp. 4745-4748 (1984). The desired R₃ substituent group can then beintroduced by reacting intermediate (3a) with an appropriately reactivemolecule R₃ -X, wherein X is halogen, such as chlorine, bromine, oriodine, or its reactive equivalent, to obtain intermediate (4a). Ketal(4a) is then reconverted to the ketone (5a) to provide the desiredstarting material. ##STR7##

1-(2-(Phenyl)ethyl)-3-substituted-4-piperidine (5a) is reacted with anunsubstituted or substituted amine to form a Schiff base (6a). TheSchiff base is then reduced, for example, with sodium borohydride toyield the unsubstituted or substituted 1-phenylmethyl or1-(2-(phenyl)ethyl)-3-substituted-4- aminopiperidine compound. See forexample, S. Grossman et al., Arch. Pharm. (Weinheim) 311, p. 1010(1978). The following reaction scheme, wherein R in the compound RNH₂ isaccording to the definition of the present invention, illustrates such amethod: ##STR8##

Amine compound (7a) can be reacted with an appropriate acid halide(e.g., R₁ COCl) or an anhydride (e.g., (R₁ CO)₂ O) to introduce thedesired R₁ -carbonyl group on the nitrogen atom and thereby obtaincompound (I) of the present invention, according to the reaction schemeshown below: ##STR9##

The cis and trans isomers of compound (7a) can be separated before orafter reaction with an acid halide or anhydride, as set out above,thereby obtaining cis and trans isomers of compound (I) of the presentinvention. The separation of the cis/trans isomers can be carried outaccording to the following reaction scheme: ##STR10##

When the desired R₂ substituent group is not phenylethyl, one procedurefor preparing compounds of the present invention with different R₂groups is to remove the phenylmethyl group in compound (2), afteroxidation of the detone tot he corresponding (5b) type compound, byhydrogenolysis (for example, using hydrogen over 10% palladium oncarbon) or by reaction with 1-chloroethyl chloroformate above andreplace it with a desired R₂ group. For example, compounds of theinvention can be prepared according to the following scheme: ##STR11##

As set out above, the cis and trans isomers of compound (7b) can beseparated prior to the next step. After any such cis/trans separation,compound (7b) can be reacted with an appropriate acid halide (e.g.,RICOCl) or an anhydride (e.g., (R₁ CO)2O) to introduce the desired R₁-carbonyl group on the nitrogen atom and thereby obtain compound (I) ofthe present invention. Compound (I) can then be reacted with hydrogenover palladium on carbon or with 1-chloroethyl chloroformate accordingto the following reaction scheme to remove the phenylmethyl group andprepare piperidinyl intermediate (8): ##STR12##

The desired R₂ substituent group can then be introduced by reactingcompound (8) with an appropriately reactive molecule R₂ -X, wherein X ishalogen, such as chlorine, bromine, or iodine, or its reactiveequivalent, to obtain compound (I) of the present invention according tothe reaction scheme illustrated below: ##STR13##

The reaction of R₂ -X with a piperidinyl intermediate such as compound(8) can be conducted in an inert organic solvent such as, for example,an aromatic hydrocarbon, a ketone such as 4-methyl-2-pentanone and thelike, an ether such as 1,4-dioxane, diethylether, tetrahydofuran,1,2-dimethoxyethane and the like, or N,N-dimethylformamide oracetonitrile The addition of an appropriate base, such as an alkalimetal carbonate, may be utilized to neutralize the acid generated duringthe reaction. The addition of an iodide salt, such as an alkali metaliodide, may be appropriate. The temperature of the reaction mixture maybe raised to increase the rate of reaction when appropriate.

In an alternative procedure, the phenylmethyl group can first be removedby hydrogenolysis or by reaction with 1-chloroethyl chloroformate priorto separation of the cis/trans isomers of compound (7) to obtaincompound (I) of the present invention with the R₁ and R₂ groupsintroduced according to one of the two schemes shown below:

OR₃ OR₃ ##STR14##

In a second example of a method for preparing the compounds of thepresent invention, an intermediate such as1-(2-(phenyl)ethyl)-4-piperidineamine (10) is utilized. In this method,the primary amine is reacted with a desired group RX, where X is ahalide or its reactive equivalent, to form a secondary amine precursorof type (7). The secondary amine is then acylated with an appropriateacid halide (e.g., R₁ COCl) or an anhydride (e.g., (R₁ CO)20) tointroduce the desired R₁ -carbonyl group on the nitrogen atom. See, forexample, Y. Zhu et al., Acta Pharm. Sinica, 16, p. 199 (1981). Thefollowing reaction scheme, wherein R and R₁ are groups within thedefinition of the present invention, illustrates such a method to makecompound (I) of the present invention. ##STR15##

In a third example of a method for preparing the compounds of thepresent invention, the same intermediate, such as1-(2-(phenyl)ethyl)-4-piperidineamine (10), is utilized. In this method,the primary amine is reacted with an oxo-derivative of the group R toform a secondary amine precursor. The oxo-intermediate is reduced priorto acylation. See, for example, Langhein et al., Offenleounqschrift.234. p. 1965 (1975); Chem. Abstr. 82, 156121w (1975).

The compounds of the present invention while effective in the form ofthe free base may be formulated and administered in the form of thetherapeutically or pharmaceutically acceptable acid addition salts forpurposes of stability, convenience of crystallization, increasedsolubility and the like. These acid addition salts include inorganicacid salts such as hydrochloric, hydrobromic, sulfuric, nitric,phosphoric, perchloric acid salts and the like; and organic acid saltssuch as acetic, trifluoro-acetic, propionic, oxalic, hydroxyacetic,methoxyacetic, 2-hydroxypropanoic, 2-oxopropanoic, propanedioic,2-hydroxy-butanedioic, benzoic, 2-hydroxybenzoic,4-amino-2-hydroxy-benzoic, 3-phenyl-2-propenoic,alpha-hydroxybenzeneacetic, methanesulfonic, ethanesulfonic,benzenesulfonic, toluene-sulfonic, cyclohexanesulfamic, succinic,tartaric, citric, maleic, fumaric acid salts and the like. The preferredacid addition salts are chloride, oxalate and citrate. These acidaddition salts can be prepared by conventional methods, such as bytreatment of the free base of the inventive compound with theappropriate acid.

The compounds of the present invention, prepared in the free base form,can be combined with a pharmaceutically acceptable carrier to provide apharmaceutical composition. Suitable carriers for the free bases includepropylene glycol-alcohol-water, isotonic water, sterile water forinjection (USP), emulphor^(TM) -alcohol-water, cremophor-EL^(TM) orother suitable carriers known to those skilled in the art.

The compounds of the present invention, prepared in the pharmaceuticallyacceptable acid addition salt form, can also be combined with apharmaceutically acceptable carrier to provide a pharmaceuticalcomposition. Suitable carriers for the acid addition salts includeisotonic water, sterile water for injection (USP), alone or incombination with other solubilizing agents such as ethanol, propyleneglycol, or other conventional solubilizing agents known to those skilledin the art.

Of course, the type of carrier will vary depending upon the mode ofadministration desired for the pharmaceutical composition as isconventional in the art. A preferred carrier is an isotonic aqueoussolution of the inventive compound.

The compounds of the present invention can be administered to mammals,e.g., animals or humans, in amounts effective to provide the desiredanalgesic therapeutic effect or to reverse the actions of an opiateanalgesic. Since the activity of the compounds and the degree of thedesired therapeutic effect vary, the dosage level of the compoundemployed will also vary. The actual dosage administered will also bedetermined by such generally recognized factors as the body weight ofthe patient and the individual hypersensitiveness of the particularpatient. Thus, the unit dosage for a particular patient (man) can be aslow as about 0.00005 mg/kg, which the practitioner may titrate to thedesired effect.

The compounds of the present invention can be administered parenterally,in the form of sterile solutions or suspensions, such as intravenously,intramuscularly or subcutaneously in the carriers previously described.The compounds may also be administered orally, in the form cf pills,tablets, capsules, troches, and the like, as well as sublingually,rectally, or transcutaneously with a suitable pharmaceuticallyacceptable carrier for that particular mode of administration as isconventional in the art.

For parenteral therapeutic administration, the compounds of the presentinvention may be incorporated into a sterile solution or suspension.These preparations should contain at least about 0.1% of the inventivecompound, by weight, but this amount may be varied to between about 0.1%and about 50% of the inventive compound, by weight of the parenteralcomposition. The exact amount of the inventive compound present in suchcompositions is such that a suitable dosage level will be obtained.Preferred compositions and preparations according to the presentinvention are prepared so that a paranteral dosage unit contains frombetween about 0.5 to about 100 milligrams of the inventive compound.

The sterile solutions or suspensions may also include the followingadjuvants: a sterile diluent, such as water for injection, salinesolution, fixed oils, polyethylene glycol, glycerine, propylene glycol,or other synthetic solvent; antibacterial agents, such as benzyl alcoholor methyl paraben; antioxidants, such as ascorbic acid or sodiummetabisulfite; chelating agents, such as ethylenediaminetetraacetic acid(EDTA); buffers, such as acetates, citrates or phosphates; and agentsfor the adjustment of tonicity, such as sodium chloride or dextrose. Theparenteral preparations may be enclosed in ampules, disposable syringes,or multiple dose vials made of glass or plastic.

The compounds of the present invention can also be administered orally.For oral therapeutic administration, the compounds may be incorporatedwith excipients and used in the form of tablets, capsules, elixirs,suspensions, syrups, wafers, chewing gums and the like. Thesepreparations should contain at least about 4% of the inventive compound,by weight, but this amount may be varied depending upon the particulardosage form from between about 4% to about 70% of the inventivecompound, by weight of the oral composition. The exact amount of thecompound present in the composition is such that a suitable dosage willbe obtained. Preferred compositions and preparations according to thepresent invention are prepared so that an oral dosage unit form containsfrom between about 5 to about 300 milligrams of the inventive compound.

The tablets, pills, capsules, troches and the like may also contain thefollowing adjuvants: a binder, such as microcrystalline cellulose, gumtragacanth or gelatine; an excipient, such as starch or lactose; adisintegrating agent, such as alginic acid, Primogel, corn starch andthe like; a lubricating agent, such as magnesium stearate or Sterotex; agliding agent, such as colloidal silicon dioxide; a sweetening agent,such as sucrose or saccharin; and a flavoring agent, such as peppermint,methyl salicylate or orange flavoring. When the dosage form is acapsule, it may additionally contain a liquid carrier such as a fattyoil. Other dosage unit forms may contain other materials which modifythe physical form of the dosage unit, such as enteric coatings. Thustablets or pills may be coated with sugar, shellac, or other entericcoating agents. A syrup may contain, in addition to the above adjuvants,sucrose as a sweetening agent, preservatives, dyes, coloring agents andflavoring agents.

It is especially advantageous to formulate the pharmaceuticalcompositions in dosage unit forms for ease of administration anduniformity cf dosage. The term dosage unit forms as used herein refersto physically discrete units suitable for use as a unitary dosage, eachunit containing a predetermined quantity of active ingredient calculatedto produce the desired therapeutic effect in association with thepharmaceutical carrier. Examples of such dosage unit forms are tablets(including scored or coated tablets), capsules, pills, powder packets,wafers, injectable solutions or suspensions, teaspoonfuls,tablespoonfuls and the like, and segregated multiples thereof.

The present invention is further illustrated by the following exampleswhich are presented for purposes of demonstrating, but not limiting, thepreparation of the compounds and compositions of this invention. Relatedmethods for preparing compounds of the type of the present invention aredisclosed in U.S. Pat. No. 4,584,303, which disclosure is incorporatedherein by reference.

EXAMPLE 1

This Example illustrates the preparation of the intermediate1-phenylmethyl-3-hydroxy-4,4-dimethoxypiperidine (3b).

1-Phenylmethyl-4-piperidone (18.92g, 100 mmol) in 40ml of methanol wasadded slowly over a period of 15 minutes to a solution of potassiumhydroxide (16.83g, 100 mmol) in I50ml of methanol at 0° C. Iodobenzenediacetate (35.43g, 11O mmol) was then added to the mixture in portionsover a period of thirty minutes. The reaction mixture was stirred atroom temperature overnight. The mixture was then concentrated undervacuum to remove the excess of methanol and the crude residue wasdiluted with a mixture cf water (500ml) and dichloromethane (300ml). Thedichloromethane layer was separated and the aqueous phase was againextracted with 150ml of dichloromethane. The combined organic layerswere dried over sodium sulfate and concentrated under vacuum. The cruderesidue was dissolved in 100ml of hexane and crystallized. The solid waswashed with 30ml of hexane to yield the intermediateI-phenylmethyl-3-hydroxy-4,4-dimethoxypiperidine (3b, 6.48g, 25.8%).

EXAMPLE 2

This Example illustrates the preparation of the intermediate1-phenylmethyl-3-methoxy-4,4-dimethoxypiperidine (4b).

1-Phenylmethyl-3-hydroxy-4,4-dimethoxypiperidine (3b, 5.5g, 22 mmol)from Example 1 in 30ml of dimethylformamide was added slowly to astirred suspension of sodium hydride (0.81g, 27 mmol, 80% oilsuspension) in 100ml of dimethylformamide. The reaction mixture waswarmed to 60° C. for 2 hours, then cooled to 0° C. whereupon methyliodide (3.8g, 27 mmol) was slowly added to the mixture. The reactionmixture was stirred overnight at room temperature then quenched with10ml of 10% sodium hydroxide solution. The reaction mixture wasconcentrated under vacuum, the residue slurried in 300ml of water andthe aqueous mixture extracted with 3×100ml of ether. The combinedorganic layers were dried over magnesium sulfate, concentrated undervacuum, then purified by column chromatography (alumina; ethylacetate/hexane; 2.5:1) to yield the intermediate1-phenylmethyl-3-methoxy-4,4-dimethoxypiperidine (4b, 3.77g, 64.6%, Rf0.63).

EXAMPLE 3

This Example illustrates the preparation of the intermediateI-phenylmethyl-3-methoxy-4-piperidone (5b).

1-phenylmethyl-3-methoxy-4,4-dimethoxypiperidine (4b, 2.22g, 8.36 mmol)from Example 2 and p-toluenesulfonic acid (3.15g, 16.6 mmol) was heatedto reflux in acetone (100ml) for three hours. After being cooled, thereaction solution was concentrated under vacuum, then slurried in 40mlof 10% sodium hydroxide solution. The aqueous mixture was extracted with2×60ml of ether, the combined organic layers were dried over magnesiumsulfate, then concentrated under vacuum. The crude residue was purifiedby chromatography (silica gel; ethyl acetate/hexane; 1:1) to provide theintermediate 1-phenylmethyl-3-methoxy-4-piperidone (5b, 1.66g, 90%).

EXAMPLE 4

This Example illustrates the preparation of the intermediate1-phenylmethyl-3-methoxy-4-phenylaminopiperidine (7b).

Sodium cyanoborohydride (0.17g, 27 mmol) and 5.2g of 3A molecular sieveswere slowly added at room temperature to a stirred solution of1-phenylmethyl-3-methoxy-4-piperidone (5b, Ig, 4.56 mmol) from Example 3in 40ml of methanol, 2.55g (27 mmol) of aniline and 3.57ml of 2.55Nhydrochloric acid in methanol. The reaction mixture was stirred at roomtemperature for 3 days, after which time the molecular sieves werefiltered off and the solution was made acidic with 10ml of 10%hydrochloric acid. The methanol was evaporated under vacuum and theresidue was diluted with 20ml of water, then extracted with ether(50ml). The aqueous layer was then made alkaline with 10% sodiumhydroxide solution and extracted with 3×100ml of ether. The combinedorganic layers were dried, then concentrated under vacuum and purifiedby column chromatography (silica gel; ethyl acetate/hexane; 1:1) toyield the intermediatescis-1-phenylmethyl-3-methoxy-4phenylaminopiperidine (7b, 0.52g, 38.23%)and trans-1-phenylmethyl-3-methoxy-4-phenylaminopiperidine (7b, 0.05g,3.7%).

EXAMPLE 5

This Example illustrates the preparation of a compound of the presentinvention cis-N-phenyl-N-(1-phenylmethyl-3-methoxy-4-piperidinyl)propanamide (I).

Propionyl chloride (0.77g, 8.3 mmol) was added tocis-1-phenylmethyl-3-methoxy-4-phenylaminopiperidine (7b, 1.6g, 5.3mmol) from Example 4 in 30ml of dichloromethane. The reaction solutionwas stirred at room temperature overnight and subsequently diluted with20ml of 10% sodium hydroxide solution. The organic layer was separatedand the aqueous layer was extracted with 2×50ml of dichloromethane. Thecombined organic layers were dried and concentrated under vacuum toyield 1.84g (99%) of crudecis-N-phenyl-N-(1-phenylmethyl-3-methoxy-4-piperidinyl) propanamide (I).

EXAMPLE 6

This Example illustrates the preparation of the intermediatecis-N-phenyl-N-(3-methoxy-4piperidinyl) propanamide (8) for thepreparation of compounds having different R₂ substituent groups.

cis-N-Phenyl-N-(I-phenylmethyl-3-methoxy-4piperidinyl) propanamide (I,1.84g, 5.22 mmol) from Example 5 was hydrogenated in 300ml of methanolusing 0.5mg of Pd(OH) as catalyst over a period of 4 hours. After theusual work-up, a quantitative yield of crude intermediatecis-N-phenyl-N-(3-methoxy-4-piperidinyl)propanamide (8) was obtained.

EXAMPLE 7

This Example illustrates the preparation of another compound of thepresent invention cis-N-phenyl-N-(1-phenylethyl-3-methoxy-4-piperidinyl)propanamide (I).

cis-N-Phenyl-N-(3-methoxy-4-piperidinyl)propanamide (8, 0.5g, 1.9 mmol)from Example 6, phenylethyl bromide (0.40g, 2.2 mmol) and 2.76g (I9mmol) of potassium carbonate in 100ml of acetonitrile were heated toreflux overnight. The reaction solution was concentrated under vacuumand the crude residue was purified by chromatography (silica gel; ethylacetate) to yield 0.43g (62%, Rf 0.326) of purecis-N-phenyl-N-(1-phenylethyl-3-methoxy-4-piperidinyl) propanamide (I).

EXAMPLES 8-38

Further examples of compounds within the scope of the present inventionwhich may be prepared by procedures analogous to those described aboveinclude:

cis-N-(phenyl)-N-[1-(2-(2H-tetrazol-2-yl)-ethyl)-3-methoxy-4-piperidinyl]propanamide

cis-N-(phenyl)-N-[l-(2-(I,3-dihydro-I,3-dioxo-2H-isoindol-2-yl)ethyl)-3-methoxy-4-piperidinyl]methoxyacetamide

cis-N-(phenyl)-N-[1-(2(phenyl)ethyl)3-methoxy-4-piperidinyl]propanamide

cis-N-(phenyl)-N-[1-(2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl)-3-methoxy-4-piperidinyl]propanamide

cis™N-(phenyl)N-[1-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl)-3-methoxy-4-piperidinyl]propanaide

cis-N-(2-fluorophenyl)-N-[1-(2-(phenyl)ethyl)-3-methoxy-4-piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[l-(2-(1,3-dihydro1,3-dioxo-2H-isoindol-2-yl)ethyl)-3-methoxy-4piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[1-(2-(2H-tetrazol-2-yl)-ethyl)-3-methoxy-4-piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[1-(2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl)-3-methoxy-4piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[1-(2-(2-thienyl)-ethyl)-3-methoxy-4-piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[1-(2-(1,3-dihydro1,3-dioxo-2H-isoindol-2-yl)ethyl)-3-methoxy-4piperidinyl]propanamid

cis-N-(2-fluorophenyl)-N-[1-(2-(1,3-dihydro1,3-dioxo-2H-isoindol-2-yl)ethyl)-3-methoxy-4piperidinyl]propanamide

cis-N-(2-fluorophenyl)-N-[1-(2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl)-3-methoxy-4piperidinyl]propanamide

trans-N-(2-fluorophenyl)-N-[1-(2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl)-3-methoxy-4piperidinyl]methoxyacetamide

trans-N-(2-fluorophenyl)-N-[I-(2-(4-ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-yl)ethyl)-3-methoxy-4piperidinyl]propanamide

cis-N-(2-fluorophenyl)-N-[1-(2-(phenyl)ethyl)-3-methoxy-4-piperidinyl]propanamide

trans-N-(2-fluorophenyl)-N-[1-(2-(phenyl)-ethyl)-3-methoxy-4-piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[I-(2-(2-thienyl)-ethyl)-3-methoxy-4-piperidinyl]propanamide

trans-N-(2-fluorophenyl)-N-[1-(2-(2-thienyl)-ethyl)-3-methoxy-4-piperidinyl]methoxyacetamide

cis-N-(phenyl)-N-[1-(phenylmethyl)-3-methoxy-4piperidinyl]methoxyacetamide

cis-N-(phenyl)-N-[1-(2-(3-ethyl-2,3-dihydro-2-oxo-1H-benzimidazol-1-yl)ethyl)-3-methoxy-4-piperidinyl]methoxyacetamide

trans-N-(2-fluorophenyl)-N-[1-(2-(1,3-dihydro1,3-dioxo-2H-isoindol-2-yl)ethyl)-3-methoxy-4piperidinyl]propanamidetrans-N-(2-fluorophenyl)-N-[I-(2-(2-thienyl)-ethyl)-3-methoxy-4-piperidinyl]propanamide

trans-N-(2-fluorophenyl)-N-[1-(2-(phenyl)-ethyl)-3-methoxy-4-piperidinyl]propanamide

trans-N-(phenyl)-N-[1-(2-(1,3-dihydro-1,3-dioxo-2H-isoindol-2-yl)ethyl)-3-methoxy-4-piperidinyl]propanamide

cis-N-(phenyl)-N-[1-(2-(4-ethyl-4,5-dihydro-5-1H-tetrazol-l-yl)ethyl)-3-methoxy-4-piperidinyl]ethoxyacetamide

cis-N-(phenyl)-N-[I-(2-(phenyl)ethyl)-3-ethoxy-4-piperidinyl]methoxyacetamide

cis-N-(phenyl)-N-[1-(2-(phenyl)ethyl)-3-methoxy-4-piperidinyl]propanamid

cis-N-(2-fluorophenyl)-N-[1-(phenylmethyl)-3-phenylmethoxy-4-piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[I-(2-(phenyl)ethyl)-3-phenylmethoxy-4-piperidinyl]methoxyacetamide

cis-N-(2-fluorophenyl)-N-[1-(2-(phenyl)ethyl)-3-hydroxy-4-piperidinyl]propanamide

EXAMPLE 39

A pharmaceutical composition for parenteral or intravenous analgesicadministration can be prepared from the following ingredients:

    ______________________________________                                        COMPONENTS              AMOUNTS                                               ______________________________________                                        cis-N-(phenyl)-N-[1-(2-(2H-tetrazol-                                                                   1 mg                                                 2-yl)-ethyl)-3-methoxy-4-piperidinyl]-                                        propanamide                                                                   isotonic water          10 liters                                             ______________________________________                                    

Of course, other compounds of this invention such as those set out inExamples 8-38 may be substituted forcis-N-(phenyl)-N-[I-(2-(2H-tetrazol-2-yl)-ethyl)-3-methoxy-4-piperidinyl]propanamidewith the relative amount of such other compounds in the compositionsdepending upon their analgesic activity.

EXAMPLE 40

A number of compounds in accordance with the present invention weretested for their analgesic properties. Specifically, the acid additionsalts of the compounds, tested in accordance with the invention, weredissolved in sterile water for injection, USP, to form a solution, theconcentration of which may vary from 0.00001 mg/ml to 5 mg/ml. Thesolution was administered intravenously into a mouse tail vain. The ED₅₀values were obtained from the mouse hot plate analgesia test (58° C.) asdescribed in Domer, Floyd R., Animal Experiments in PharmacologicalAnalysis, Charles C. Thomas, Springfield, 1971, p. 283. The compoundslisted in Table 1 were tested by this procedure and found to have theactivities listed in the columns on the right side of Table 1.

                  TABLE 1                                                         ______________________________________                                                               M.P. °C.                                                               (oxalate ED.sub.50                                     COMPOUNDS              salt)    Mg/Kg                                         ______________________________________                                         1. cis-N-(phenyl)-N-[1-(2-(2H-tetrazol-2-                                                               174-176  2.2                                           yl)ethyl)-3-methoxy-4-piperidinyl]-                                           propanamide                                                                2. cis-N-(phenyl)-N-[1-(2-(1,3-dihydro-1,3-                                                              95-96   I*                                            dioxo-2H-isoindol-2-yl)ethyl)-3-methoxy-                                      4-piperidinyl]methoxyacetamide                                             3. cis-N-(phenyl)-N-[1-(2-(phenyl)ethyl)-                                                               183-184  0.00064                                       3-methoxy-4-piperidinyl]propanamide                                        4. cis-N-(phenyl)-N-[1-(2-(4-ethyl-4,5-                                                                 163-165  0.384                                         dihydro-5-oxo-1H-tetrazol-1-yl)ethyl)-3-                                      methoxy-4-piperidinyl]propanamide                                          5. cis-N-(phenyl)-N-[1-(2-(1,3-dihydro-1,3-                                                             184-185  0.768                                         dioxo-2H-isoindol-2-yl)ethyl)-3-methoxy-                                      4-piperidinyl]propanamide                                                  6. cis-N-(2-fluorophenyl)-N-[1-(2-(phenyl)-                                                             184-185  0.000641                                      ethyl)-3-methoxy-4-piperidinyl]-                                              methoxyacetamide                                                           7. cis-N-(2-fluorophenyl)-N-[1-(2-(1,3-                                                                 126-128  I                                             dihydro-1,3-dioxo-2H-isoindol-2-yl)-                                          ethyl)-3-methoxy-4-piperidinyl]-                                              methoxyacetamide                                                           8. cis-N-(2-fluorophenyl)-N-[1-(2-(2H-                                                                  144-145  I                                             tetrazol-2-yl)-ethyl)-3-methoxy-4-                                            piperidinyl]methoxyacetamide                                               9. cis-N-(2-fluorophenyl)-N-[1-(2-(4-ethyl-                                                              93-95   0.554                                         4,5-dihydro-5-oxo-1H-tetrazol-1-yl)-                                          ethyl)-3-methoxy-4-piperidinyl]-                                              methoxyacetamide                                                          10. cis-N-(2-fluorophenyl)-N-[1-(2-(2-                                                                   186-187  0.00046                                       thienyl)ethyl)-3-methoxy-4-piperidinyl]-                                      methoxyacetamide                                                          11. cis-N-(2-fluorophenyl)-N-[1-(2-(1,3-                                                                 112-114  0.489                                         dihydro-1,3-dioxo-2H-isoindol-2-yl)-                                          ethyl)-3-methoxy-4-piperidinyl]-                                              propanamide                                                               12. cis-N-(2-fluorophenyl)-N-[1-(2-(1,3-                                                                  96-98   I                                             dihydro-1,3-dioxo-2H-isoindol-2-yl)-                                          ethyl)-3-methoxy-4-piperidinyl]-                                              propanamide                                                               13. cis-N-(2-fluorophenyl)-N-[1-(2-(4-ethyl-                                                             144-146  0.124                                         4,5-dihydro-5-oxo-1H-tetrazol-1-yl)-                                          ethyl)-3-methoxy-4-piperidinyl]  -                                            propanamide                                                               14. trans-N-(2-fluorophenyl)-N-[1-(2-(4-                                                                 150-152  I                                             ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-                                        yl)ethyl)-3-methoxy-4-piperidinyl]-                                           methoxyacetamide                                                          15. trans-N-(2-fluorophenyl)-N-[1-(2-(4-                                                                 139-141  I                                             ethyl-4,5-dihydro-5-oxo-1H-tetrazol-1-                                        yl)ethyl)-3-methoxy-4-piperidinyl]-                                           propanamide                                                               16. cis-N-(2-flurophenyl)-N-[1-(2-(phenyl)-                                                              195-197  0.00091                                       ethyl)-3-methoxy-4-piperidinyl]-                                              propanamide                                                               17. trans-N-(2-fluorophenyl)-N-[1-(2-                                                                    144-145  0.047                                         (phenyl)ethyl)-3-methoxy-4-piperidinyl]-                                      methoxyacetamide                                                          18. cis-N-(2-fluorophenyl)-N-[1-(2-(2-                                                                   183-185  0.0013                                        thienyl)ethyl)-3-methoxy-4-piperidinyl]-                                      propanamide                                                               19. trans-N-(2-fluorophenyl)-N-[1-(2-(2-                                                                 134-135  0.015                                         thienyl)ethyl)-3-methoxy-4-piperidinyl]-                                      methoxyacetamide                                                          20. cis-N-(phenyl)-N-[1-(phenylmethyl)-3-                                                                126-127  I                                             methoxy-4-piperidinyl]-                                                       methoxyacetamide                                                          21. cis-N-(phenyl)-N-[1-(2-(3-ethyl-2,3-                                                                 118-119  0.538                                         dihydro-2-oxo-1H-benzimidazol-1-yl)-                                          ethyl)-3-methoxy-4-piperidinyl]-                                              methoxyacetamide                                                          22. trans-N-(2-fluorophenyl)-N-[1-(2-(1,3-                                                               126-128  0.913                                         dihydro-1,3-dioxo-2H-isoindol-2-yl)-                                          ethyl)-3-methoxy-4-piperidinyl]-                                              propanamide                                                               23. trans-N-(2-fluorophenyl)-N-[1-(2-(2-                                                                 155-157  0.01                                          thienyl)ethyl)-3-methoxy-4-piperidinyl]-                                      propanamide                                                               24. trans-N-(2-fluorophenyl)-N-[1-(2-                                                                    170-173  0.0019                                        (phenyl)ethyl)-3-methoxy-4-piperidinyl]-                                      propanamide                                                               25. trans-N-(phenyl)-N-[1-(2-(1,3-dihydro-                                                               124-126  I                                             1,3-dioxo-2H-isoindol-2-yl)ethyl)-3-                                          methoxy-4-piperidinyl]propanamide                                         26. cis-N-(phenyl)-N-[1-(2-(4-ethyl-4,5-                                                                 158-160  I                                             dihydro-5-oxo-1H-tetrazol-1-yl)ethyl)-3-                                      methoxy-4-piperidinyl]-                                                       methoxyacetamide                                                          27. cis-N-(phenyl)-N-[1-(2-(phenyl)ethyl)-                                                               165-167  0.0027                                        3-methoxy-4-piperidinyl]-                                                     methoxyacetamide                                                          28. cis-N-(phenyl)-N-[  1-(2-(phenyl)ethyl)-                                                             153-154  0.525                                         3-methoxy-4-piperidinyl]propanamide                                       29. cis-N-(2-fluorophenyl)-N-[1-                                                                         156-158  I                                             (phenylmethyl)-3-phenylmethoxy-4-                                             piperidinyl]methoxyacetamide                                              30. cis-N-(2-fluorophenyl)-N-[1-(2-(phenyl)-                                                             171-172  0.724                                         ethyl)-3-phenylmethoxy-4-piperidinyl]-                                        methoxyacetamide                                                          31. cis-N-(2-fluorophenyl)-N-[1-(2-(phenyl)-                                                             153-154  0.525                                         ethyl)-3-hydroxy-4-piperidinyl]-                                              propanamide                                                               ______________________________________                                         * = Inactive                                                             

It will be understood that the embodiments described herein are merelyexemplary and that a person skilled in the art may make many variationsand modifications without departing from the spirit and scope of theinvention. All such modifications and variations are intended to beincluded within the scope of the invention as defined in the appendedclaims.

We claim:
 1. A compound having the formula: ##STR16## an opticallyactive isomeric form thereof, a cis/trans isomeric form thereof or apharmaceutically acceptable acid addition said thereof, wherein:R isselected from the group consisting of phenyl and substituted phenyl,wherein the substituents on the phenyl group are selected from the groupconsisting of halogen, lower-alkyl lower-alkoxy, and combinationsthereof: R₁ is selected from the group consisting of lower-alkyl,lower-alkenyl, and lower-aloxy lower-alkyl, each alkyl group having form1 to 6 carbon atoms: R₂ is substituted or unsubstituted phenyllower-aklyl; and R₃ is selected from the group consisting of hydrogen,lower-alkyl and phenylmethyl.
 2. A compound according to claim 1,wherein R is selected from the group consisting of phenyl,2-fluorophenyl and 2-methoxyphenyl.
 3. A compound according to claim 1,wherein R₁ is selected from the group consisting of methyl, ethyl,methoxymethyl and 1-methoxyethyl.
 4. A compound according to claim 1,wherein R₂ is selected from the group consisting of substituted orunsubstitued phenylmethyl and 2-phenylethyl.
 5. A compound according toclaim 1, wherein R₃ is selected from the group consisting of hydrogen,methyl and phenylmethyl.
 6. A compound according to claim 1, whichcomprises cis-N-(2-fluorophenyl)-N-[1-(2-phenyl)ethyl)-3-methoxy-4-piperidinyl]-methoxyacetamide or a pharmaceuticallyacceptable salt thereof.
 7. A compound according to claim 1, whichcomprises cis-N-(phenyl)-N-[1-(2-(phenyl)ethyl)-3-methoxy-4-piperidinyl]-propanamide, or a pharmaceuticallyacceptable addition salt thereof.
 8. A compound according to claim 1,which comprises cis-N-(2-fluorophenyl)-N-[1-(2-(phenyl)ethyl)-3-methoxy-4-piperidinyl]-propanamide, or a pharmaceuticallyacceptable addition salt thereof.
 9. A narcotic analgesic compositioncomprising a non-toxic pharmaceutically acceptable carrier and ananalgesically effective amount of a compound having the formula:##STR17## optically active isomeric form thereof, a cis/trans isomericform thereof or a pharmaceutically acceptable acid addition saltthereof, wherein:R is selected from the group consisting of phenyl andsubstituted phenyl, wherein the substituents on the phenyl group areselected from the group consisting of halogen, lower-alkyl lower-alkoxy,and combination thereof: R₁ is selected from the group consisting oflower-alkyl, lower-alkenyl, and lower-alkoxy lower-aklyl, each alkylgroup having from 1 to 6 carbon atoms; R₂ is substituted orunsubstituted phenyl lower-aklyl; and R₃ is selected from the groupconsisting of hydrogen, lower-alkyl and phenylmethyl.
 10. A compositionaccording to claim 9, wherein R is selected from the group consisting ofphenyl 2-fluorophenyl and 2-methoxyphenyl.
 11. A composition accordingto claim 9, wherein R₁ is selected from the group consisting of methyl,ethyl, methoxymethyl and 1-methoxyethyl.
 12. A composition according toclaim 9, wherein R₂ is selected from the group consisting of substitutedor unsubstituted phenylmethyl and 2-phenylethyl.
 13. A compositionaccording to claim 9, wherein R₃ is selected from the group consistingof hydrogen, methyl and phenylmethyl.
 14. A composition according toclaim 9, which comprises cis-N-(2fluorophenyl)-N-[1-(2-phenyl)ethyl)3-methoxy-4-piperidinyl]-methoxyacetamide or a pharmaceuticallyacceptable salt thereof.
 15. A composition according to claim 9, whichcomprises cis-N-(phenyl)-N-[1-(2-(phenyl) ethyl)-3-methoxy4-piperidinyl]-propanamide, or a pharmaceutically acceptable additionsalt thereof.
 16. A composition according to claim 9, which comprisescis-N-(2-fluorophenyl)-N-[1-(2(phenyl)ethyl)-3-methoxy-4-piperidinyl]-propanamide, or a pharmaceuticallyacceptable addition salt thereof.
 17. A method of producing analgesia ina mammal comprising administering to the mammal in need thereof ananalgesically effective amount of a compound having the formula:##STR18## an optically active isomeric form thereof, a cis/transisomeric form thereof or a pharmaceutically acceptable acid additionsalt thereof, wherein:R is selected from the group consisting of phenyland substituted phenyl, wherein the substituents on the phenyl group areselected from the group consisting of halogen, lower-alkyl lower-alkoxy,and combinations thereof; R₁ is selected from the group consisting oflower-alkyl, lower-alkenyl, and lower-alkoxy lower-alkyl, each alkylgroup having from 1 to 6 carbon atoms; R₂ is substituted orunsubstituted phenyl lower-alkyl; and R₃ is selected from the groupconsisting of hydrogen, lower-alkyl and phenylmethyl.
 18. A methodaccording to claim 17, wherein R₂ is selected from the group consistingof substituted or unsubstituted phenylmethyl and 2-phenylethyl.
 19. Amethod according to claim 17, which comprisescis-N-(2-fluorophenyl)-N-[1-(2-phenyl)ethyl)-3-methoxy-4-piperidinyl]-methoxyacetamide or a pharmaceuticallyacceptable salt thereof.
 20. A method according to claim 17, whichcomprises cis-N-(phenyl)-N-[1-(2(phenyl)ethyl)-3-methoxy-4-piperidinyl]-propanamide, or a pharmaceuticallyacceptable addition salt thereof.
 21. A method according to claim 17,which comprises cis-N-(2-fluorophenyl)-N-[1-(2-(pheny)ethyl)3-methoxy-4-piperidinyl]-propanamide, or a pharmaceuticallyacceptable addition salt thereof.